Patients with malignant hematological disorders resistant to conventional doses of chemotherapy and/or radiation may be treated by autologous or allogeneic bone marrow transplantation. Bone marrow transplantation (BMT) makes it possible to administer to patients with resistant disease high, "supra-lethal," combinations of chemotherapy and radiation, ignoring the irreversible toxicity of such therapeutic combinations on the normal bone marrow compartment. Nevertheless, such "debulking" of a patient's tumor(s) can leave a fraction of residual malignant cells that may lead to disease relapse. Several lines of evidence suggest that a significant proportion of the beneficial effect of allogeneic BMT (i.e., BMT from an individual not genetically identical to the host patient) stems from cell-mediated interactions of immune cells of donor origin against residual tumor cells in the host that have escaped the chemoradiotherapy debulking regimen.
Following allogeneic BMT, the incidence of relapse is significantly lower in leukemia patients with clinical manifestations of acute or chronic graft versus host disease (GVHD), as compared with patients with no GVHD, indicating that immune-mediated allogeneic interactions of immunocompetent cells of donor origin against the host are also accompanied by graft vs. leukemia (GVL) effects. Weiden et al., N. Engl. J. Med. 300: 1068 (1979); Weiden et al., N. Engl. J. Med. 304: 1529-33 (1981); Weiden et al., Transplantation 13: 248-51 (1981); Barrett et al., Blood 74: 862 (1989); Sullivan et al., Blood 73: 1720 (1989); Horowitz et al., Blood 75: 555 (1990); Slavin et al., Bone Marrow Transplant. 6: 155-61 (1990).
Higher relapse rates seem to occur in patients undergoing allogeneic BMT with T-lymphocyte depletion for prevention of GVHD, compared to recipients of non-T cell depleted marrow allografts, regardless of the severity of GVHD. Horowitz et al., Blood 75: 555 (1990); Slavin et al., Bone Marrow Transplant. 6: 1559-61 (1990); Goldman et al., Ann. Inter. Med. 108: 806-14 (1988); Ringden and Horowitz, Transplant. Proc. 21: 2989-92 (1989); Goldman et al., Ann. Int. Med. 108: 806 (1988). Likewise, relapse rates in patients with acute leukemia or chronic myeloid leukemia reconstituted by bone marrow grafts obtained from an identical twin (syngeneic grafts) are significantly higher than in those reconstituted by bone marrow cells obtained from an HLA-identical but non-syngeneic sibling. Ringden and Horowitz, Transplant. Proc. 21: 2989-92 (1989). Similarly, relapse rates following transplantation of the patient's own (autologous) marrow, even following adequate purging in vitro for elimination of residual leukemia cells, are significantly higher than following allogeneic BMT. Armitage, Curr. Opinion in Hematol. 1993: 240-45 (1993). Thus, the less-than optimal results with autologous BMT (ABMT) are similar to the results seen with syngeneic marrow transplantation. All of the above data suggests that in practical terms GVHD or GVHD-potential correlates with a lower incidence of relapse.
Allogeneic donor cells may also play a role against lymphoma, as shown in experimental animals, Slavin et al., Cancer Immunol. Immunother. 11: 155-58 (1981), and humans. Phillips et al., J. Clin. Oncol. 4: 480-88 (1986); Ernst et al., Proc. of the 4th International Conference on Lymphoma, Lugano 1990, Abstract #P35; Chopra et al., J. Clin. Oncol. 10: 1690-95 (1992). As shown in experimental animals, graft-versus-tumor effects (GVT), similar to graft-versus-leukemia effects (GVL), may occur following BMT, independently of GVHD. Moscovitch and Slavin, J. Immunol. 132: 997-1000 (1984).
Although GVHD-associated anti-leukemia effector mechanisms may be of benefit in BMT, nevertheless GVHD represents one of the major obstacles in allogeneic BMT, even among perfectly HLA-matched siblings. Acute GVHD develops in the majority of recipients of allogeneic BMT, with clinically significant manifestations in 26-64% of the recipients despite optimal post-transplant immunosuppressive prophylaxis. Storb et al., Blood 73: 1729 (1989). Chronic GVHD may occur in up to 45% of long term survivors. Storb et al., Blood 73: 1729 (1989). There is no satisfactory therapy for patients with established GVHD and hence patients with severe manifestations of acute or chronic forms of the disease are prone to develop multisystem complications that may require frequent hospitalizations, leading to poor quality of life and occasionally serious or even fatal complications.
GVHD following allogeneic BMT can be prevented by adequate pretransplant T-lymphocyte depletion, using no post-transplant anti-GVHD prophylaxis. Reisner et al., In: Slavin, S (ed.), Tolerance in Bone Marrow and Organ Transplantation. Elsevier, Amsterdam (1984), p. 293; Waldmann et al., Lancet 2: 483-85 (1984); Slavin et al., Transplant. Proc. 17: 465-67 (1985). BMT without GVHD represents a better tolerated procedure that may necessitate shorter hospitalization with superior subjective immediate outcome following allogeneic BMT. In addition, the quality of life of long-term survivors without GVHD is clearly better than for those patients with severe acute or chronic GVHD.
Unfortunately, the advantages of GVHD-free-allogeneic BMT are counterbalanced by other serious complications due to untoward effects of T-lymphocyte depletion, such as increased incidence of graft rejection, occurring in 10-30% of recipients, as well as increased rates of tumor relapse. Martin et al., Bone Marrow Transplant. 3: 445 (1988); Kernan et al., Transplantation 43: 842 (1987); Waldmann et al., Lancet 2: 483-85 (1984); Slavin et al., Transplant. Proc. 17: 465-67 (1985). Consequently, there seems to be no clear evidence to date for a significant overall benefit of GVHD prevention by T-lymphocyte depletion.
Clearly, it would be a significant advance in the art to be able to combine the benefits of minimal or controllable GVHD risk following ABMT or ASCT with induction of graft-versus-malignant cell response that may be associated with GVHD following allogeneic BMT.